Increased sympathetic nervous activity (SNA) elevates venomotor tone in DOCA-salt hypertension. We studied the mechanisms by which the SNA increases venomotor tone in DOCA-salt hypertension by making in situ intracellular recordings of vascular smooth muscle cell (VSMC) membrane potential (Em) and measurement of outside diameter (OD) in mesenteric veins (MV) and mesenteric arteries (MA) of anesthetized rats. We also studied norepinephrine (NE) and endothelin-1 (ET-1)-induced increases in MA or MV perfusion pressure (PP) in vitro. Em in DOCA-salt MV was depolarized compared to sham MV. Prazosin hyperpolarized VSMC Em in DOCA-salt but not in sham MV. NE concentration-response curves (CRCs) for OD decreases in MV from DOCA-salt rats were left-shifted with an increased maximum response (Emax) compared to sham MV. NE CRCs for OD decreases in MA were right-shifted with reduced Emax in DOCA-salt compared to sham rats. ET-1 CRCs were similar in DOCA-salt and sham MV, but were right-shifted with reduced Emax in DOCA-salt MA. NE CRCs for MAPP increases were left-shifted without a change in Emax in DOCA-salt rats. NE did not change MVPP. MAPP and MVPP for ET-1 CRCs were similar in sham and DOCA-salt rats, but Emax for MAPP was reduced in DOCA-salt rats. Hematoxylin-staining revealed hypertrophy in DOCA-salt MA but not in MV. We conclude that there is increased reactivity to NE released from the SNS in DOCA-salt MV, which causes VSMC depolarization and increased venomotor tone. In DOCA-salt rats, in vivo ET-1 reactivity is maintained in MV, but reduced in MA.